|Year : 2020 | Volume
| Issue : 2 | Page : 254-263
Leptomeningeal metastasis from extracranial solid tumors
Dilip Harindran Vallathol, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Nandini Menon, Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Submission||02-Feb-2020|
|Date of Decision||21-Feb-2020|
|Date of Acceptance||24-Feb-2020|
|Date of Web Publication||19-Jun-2020|
Dr. Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Leptomeningeal metastasis (LM) is a dreaded complication associated with solid tumors which is increasing due to the advances in cancer-directed therapy. Proper diagnostic and treatment criteria are still not established for the handling of LM. This article aims to help outline a management plan for LM.
Methods: A systematic review of the articles on LM and solid tumors was done in PubMed for the past 15 years and eligible articles were eligible articles were considered. The articles related to hematological malignancies and brain tumors were excluded.
Results and Discussion: LM usually requires a strong suspicion based on the natural history of the disease and symptoms for diagnosis. Symptomatology, cerebrospinal fluid (CSF) examination, and magnetic resonance imaging aid in the diagnosis. The treatment involves a multimodal institution of intra-CSF therapy, systemic chemotherapy, craniospinal irradiation, and surgical interventions for relief of symptoms. The prognosis is usually poor despite treatment and expected survival is between 4 and 6 months.
Conclusion: The different options for the treatment of LM should be discussed in a multidisciplinary clinic. The treatment must be decided based on the neurological and general health condition of the patient, previous lines of treatment, and the presence of other metastatic sites. The improvement of levels of evidence for the various therapeutic procedures for patients with LM requires dedicated trials.
Keywords: Leptomeningeal metastasis, multidisciplinary clinic, prognosis, systematic review
|How to cite this article:|
Vallathol DH, Patil VM, Noronha V, Joshi A, Menon N, Prabhash K. Leptomeningeal metastasis from extracranial solid tumors. Cancer Res Stat Treat 2020;3:254-63
|How to cite this URL:|
Vallathol DH, Patil VM, Noronha V, Joshi A, Menon N, Prabhash K. Leptomeningeal metastasis from extracranial solid tumors. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 18];3:254-63. Available from: http://www.crstonline.com/text.asp?2020/3/2/254/287247
| Introduction|| |
Leptomeningeal metastasis (LM) is due to the spread of cancer cells to the pia and arachnoid mater (which constitute the leptomeninges), subarachnoid space, and other cerebrospinal fluid (CSF) compartments., LM is seen in approximately 5%–10% of patients with solid cancer, usually related to progressive systemic spread during the course of disease. Improved diagnostic assessment and treatment have resulted in an increase in the occurrence of LM. The common extracranial solid tumors leading to LM are breast cancer, lung cancer, and melanoma. Lately, new diagnostic methods and innovative targeted therapies have been developed that could potentially help with early diagnosis and improved treatment of LM. The main focus of this review article is LM secondary to solid primary cancers in adults, excluding those arising from the central nervous system (CNS) and hematological malignancies.
| Methods|| |
A comprehensive systematic literature search in PubMed (Cochrane and Scopus) with keywords such as “Leptomeningeal Carcinomatosis AND Solid Tumors,” “Leptomeningeal Metastasis AND Solid tumors,” and “Neoplastic Meningitis AND solid tumors” was performed. [Figure 1] shows the flowchart followed for identification of articles for review.
|Figure 1: Flowchart of the study selection process for the review of leptomeningeal metastases in patients with solid tumors|
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| Results and Discussion|| |
Epidemiology and clinical features
Roughly 5%–10% of patients with solid tumors are clinically diagnosed with LM, but as shown by the autopsy series, the occurrence of undiagnosed or asymptomatic LM with many solid tumors may be 20% or more. Lung cancer, breast cancer, melanomas, gastrointestinal cancers, and carcinoma unknown primary are the most common solid tumors leading to LM.
Resection of cerebellar parenchymal metastases has been reported to lead to the development of LM. The spillage of cancer cells directly into CSF followed by their dissemination is the assumed mechanism.,
The use of more effective adjuvant and salvage systemic therapy is a significant factor leading to a heightened occurrence of LM, which also leads to a prolongation of survival and late metastatic spread to the CNS. The poor CNS penetration of novel targeted therapies is another reason leading to an increased occurrence of LM.,
In patients with breast cancer, infiltrating lobular carcinoma and triple negative immunohistochemistry status are the factors that predispose to the development of LM.,
Between 60% and 70% of patients also display progressive systemic disease during LM diagnosis., A duration of 1.2–2.0 years has been observed between the diagnosis of the malignancy and the diagnosis of LM in extracranial solid tumors.
The location of involvement of the CNS dictates the symptoms and signs of the patients with LM. It relates to the signs and symptoms in the three domains of CNS functions, namely: (1) the cerebrum and its associated structures; (2) the cranial nerves; and (3) the spinal cord and spinal nerve roots. Cranial nerve and spinal nerve dysfunction, raised intracranial tension, or meningeal irritation are the common clinical findings. The signs and symptoms in older patients are similar to those in younger patients; hence, the diagnosis does not differ.
Based on the histology of the primary tumor, cancer cells can enter the meninges via various pathways.
Even though malignant cell spread to the arachnoid through arterial circulation is the main reason for LM, it is seen less frequently in solid tumors when compared to hematological malignancies.
Vertebral and paravertebral metastases could spread along the associated lymphatics or veins, or to the cranial nerves through the endoneural or perineural course or centripetally along the peripheral nerves.
A direct spread has also been suggested for LM from the brain parenchyma.
As there are no tests that can categorically rule out the involvement of LM, the diagnosis remains challenging.
Cerebrospinal fluid examination
CSF examination is the most effective lab-based test for the identification of LM. Irregularities such as decreased glucose, raised protein concentration, increased leukocytes, and/or increased opening pressure, are suggestive of LM.
Even though the identification of LM is generally confirmed by the presence of cancerous cells in the CSF, attributing it to a particular tumor is not possible. Moreover, an early positive CSF cytology is only seen in 45%–55% of the patients with LM.
Collection of at least 10.5 mL of non-hemorrhagic CSF sample from a site compatible with the clinical manifestations or directed by radiologic findings increases the sensitivity of CSF cytologic analysis. The collection of a second CSF sample in a similar manner improves the sensitivity of CSF cytology to 80% in patients with positive CSF.,
Several biomarkers in the CSF aid in the earlier identification of LM and monitoring therapeutic response. Tumor markers, such as the carcinoembryonic antigen for adenocarcinomas, α-fetoprotein for hepatocellular and testicular tumors, and β-human chorionic gonadotropin for choriocarcinoma and testicular tumors, are somewhat specific for LM., Monitoring the levels of tumor markers also helps in the evaluation of response to treatment.
Techniques used for the detection of circulating tumor cells in the peripheral blood like NGS have shown promise when extrapolated to the CSF., Another technique that has proved to be useful in the identification of LM from solid tumors is the rare cell capture technology. The new kid on the block, “liquid biopsy,” has also been used for diagnosis.
The study of CSF flow dynamics with 111-In-diethyle netriaminepenta-acetic acid or 99Tc-macroaggregated albumin is suggested for LM and is useful to assess the CSF flow., Approximately 30%–70% of the patients with LM have displayed abnormal CSF circulation, with blocks commonly occurring at the skull base, the spinal canal, and over the cerebral gyri and sulci., Disturbed CSF flow in LM patients has been associated with a significantly reduced survival.,
In case of a clinical suspicion, magnetic resonance imaging (MRI) of the brain and spine is recommended which could detect leptomeningeal enhancement, which is often nodular and irregular. If a lumbar puncture has been performed recently, imaging should be interpreted with proper care. The MRI sensitivity with gadolinium contrast is around 70%, and specificity is in the range of 77%–100%. An abnormal MRI is sufficient to make the diagnosis in the presence of typical clinical features. [Figure 2], [Figure 3], [Figure 4] show the typical appearance of LM on MRI imaging. [Figure 2] and [Figure 3] show the postcontrast T1-weighted image and [Figure 4] shows the postcontrast fluid-attenuated inversion recovery image depicting leptomeningeal enhancement.
|Figure 2: T1-weighted postcontrast image showing leptomeningeal enhancement in a case of leptomeningeal metastasis|
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|Figure 3: T1-weighted postcontrast image showing leptomeningeal enhancement in a case of leptomeningeal metastasis|
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|Figure 4: Postcontrast fluid-attenuated inversion recovery sequence images showing leptomeningeal enhancement in a case of leptomeningeal metastasis|
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Despite the progress made in cancer management, the survival rate for patients with LM is still low. If treated, the overall survival (OS) from the time of diagnosis is approximately 2–4 months. Progressive neurologic deterioration leads to death in untreated cases in 4–6 weeks., A Karnofsky Perfomance Status (KPS) >70, chemosensitivity of the primary malignancy, unimpaired CSF flow, CSF protein less than 50 mg/dL, and the administration of active disease control measures have been identified as favorable prognostic factors.
Poor prognostic factors identified by the National Comprehensive Cancer Network are KPS <60, severe neurological deficits, widespread systemic disease with exhausted treatment options, bulky neurological disease, and encephalopathy.,
The leading determinant of prognosis with regards to OS in LM is the type of primary cancer., Breast cancer LM has a relatively good prognosis compared to other solid tumors with a median OS ranging from 3.5–5 months., The survival of lung cancer-related LM has improved after the increased use of tyrosine kinase inhibitors (TKIs) and other targeted agents with a median survival of 3–4.3 months.
Assessing response to therapy
It is challenging to evaluate the response to treatment. It is usually done in the clinics by clinical, radiologic, and CSF evaluation. The Response Assessment in Neuro-Oncology (RANO) Group proposed a standardized assessment in 2016 [Table 1] after realizing the difficulties in assessing outcomes. The RANO criteria include imaging (usually MRI) of the brain and spine, a standard neurologic examination, and CSF evaluation. It is hoped that the criteria will be adopted as a new standard that can be included in future clinical trials to enable better assessment of the therapeutic response and comparisons across trials.
|Table 1: Proposed Response Assessment in NeuroOncology (RANO) criteria for leptomeningeal metastasis in solid tumors|
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The RANO working group has provided a symptom inventory which includes complete standardized neurological examination [Table 2] and formal radiological assessment [Table 3].
|Table 2: Neurological Examination used in the RANO criteria for a patient with leptomeningeal metastasis|
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|Table 3: Radiographic assessment used in the RANO criteria for a patient with leptomeningeal metastasis|
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Patients with LM who display progressive disease at other metastatic sites and those with limited treatment options and badly affected quality of life, due to irreversible neurologic deficits or encephalopathy, have a poor prognosis despite the use of aggressive LM-directed therapies. Such patients should probably be treated by a palliative approach.
As most systemic chemotherapy drugs have limited capacity to cross the blood–brain barrier (BBB), they are usually combined with interventions such as radiation to prolong the survival, maintain the quality of file, and prevent the deterioration of neurologic function. Even though intra-CSF therapy is often considered the gold standard, meaningful clinical trial data from these efforts are lacking.
The normal blood–brain barrier prevents the penetration of intravenously administered chemotherapeutic agents into the CNS. The intra-CSF chemotherapy acts via evasion of the blood–CSF barrier; this maximizes drug exposure in the CSF. This also causes less systemic chemotoxicity, which is a problem with intravenous administration. The lower volume of distribution of drugs in the CSF than that in the plasma ensures a higher drug concentration at a smaller dose. Most of the cytotoxic chemotherapy drugs have a longer t1/2 (halflife) in the CSF than in the plasma. This allows for prolonged CSF drug exposure. Cell cycle-specific chemotherapy agents such as methotrexate (MTX) and cytosine arabinoside (ara-C) are utilized for intra-CSF therapy due to this peculiarity. An equivalent volume of CSF (also known as isovolumetric withdrawal) should be removed before chemotherapy administration.
Agents used and modes of administration
In routine daytoday practice, methotrexate, ara-C or liposomal ara-C, and thiotepa are utilized for intraventricular/intrathecal (IT) therapy.
IT treatment is delivered by repeated lumbar punctures. Positional variation occurs with this procedure with respect to ventricular drug levels. Patients should therefore remain supine for at least one hour after IT drug injection. The Ommaya or Rickham reservoir is used in the intraventricular administration of drugs. Intraventricular reservoirs offer several advantages, including painless and relatively rapid time-efficient administration, and uniform drug distribution in the subarachnoid spaces and brain convexities.
The impact of IT therapy on neurological outcomes and survival have been described in several retrospective studies., All the 5 randomized clinical trials [Table 4] conducted in patients with LM were concentrated on IT therapy. A limitation of the studies was that the patients who were determined to be too sick for treatment were excluded from most trials and series; which could have comprised a major proportion of patients at presentation. A study by Boogerd et al. which included 35 patients with breast cancer, of which 17 were randomized to receive IT chemotherapy, and the rest to systemic chemotherapy, proved that neurologic response and survival were similar in the two arms; however, the trial accrued slowly, and was closed early. A retrospective study comprising 104 patients with LM compared patients who received systemic therapy and radiation with or without IT therapy for any solid tumor; no difference was observed in the median survival. Quality-of-life measures were not reported in either study, and the patients who received IT chemotherapy had increased treatment-related neurotoxicity. IT glucocorticoids in combination with IT chemotherapy have not shown benefit in solid-tumor-associated LM compared to hematological malignancies.
|Table 4: Randomized trials of intrathecal chemotherapy in Leptomeningeal Metastasis from solid tumors|
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A therapeutic concentration of 1 mM/mL is achieved with a dose of 12-mg intra-CSF methotrexate and maintained for 48–72 h., The ideal regimen or schedule of IT MTX administration and duration of treatment is still not known. The median OS reported in retrospective studies ranges from 3.5 to 5 months. Folinic acid (leucovorin) rescue is not routinely advised except in cases of drug overdose.,,
Ara-C is also used in IT therapy in LM similar to MTX. The low CSF cytidine deaminase leads to a much greater t1/2 of Ara-C in the CSF than in the serum.
A depot formulation of Ara-C, called liposomal Ara-C, is frequently used. It solves the problem of the short t1/2 of AraC. Liposomal Ara-C has a t1/2 of 140 h and maintains a therapeutic concentration in the CSF for 10–12 days. Therefore, unlike the normal Ara-C, it needs to be administered once every 2 weeks.
Thiotepa has the shortest t1/2 among the drugs used for IT therapy. Its CSF clearance occurs within 4 h. The pharmacologic advantage of IT thiotepa has been debated because of the rapid transcapillary movement of the drug.
Combination IT chemotherapy has no advantage in solid tumor-related LM but adds to toxicity. The cytologic response rate and median survival were similar in a single randomized controlled trial which compared IT MTX plus Ara-C and hydrocortisone (triple IT therapy); there was added toxicity in the combination arm. [Table 5] shows the summary of intrathecal therapies used for LM.
|Table 5: Summary of the intrathecal agents used is provided in the table below|
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Aseptic or chemical meningitis is a commonly observed complication in intra-CSF therapy. It is indicated by clinical symptoms and signs of meningitis as well as sterile CSF pleocytosis. The symptoms of this complication can generally be treated using corticosteroids and intravenous hydration. Quality of life studies have never been done with IT therapy. It is observed in 8%–24% cases receiving intra-CSF therapy.
Other known complications of intra-CSF chemotherapy include seizures, myelopathy, leukoencephalopathy and inadvertent subdural or epidural delivery of the drug (if administered by lumbar puncture). Myelosuppression is also displayed by up to 18% of patients, irrespective of the method of administration.
The use of prophylactic antibiotics (either IT or oral) is not recommended as per existing guidelines.
There is a break of the BBB in the setting of LM; therefore, it has been established that several chemotherapies achieve therapeutic levels in the CSF when administered systemically in this setting. Another advantage of systemic chemotherapy is that it does not depend on CSF flow for its action. It penetrates bulky disease and additionally acts on any systemically active or progressive disease. The choice of systemic chemotherapy should be guided by the type of malignancy. Options include high-dose methotrexate (more than 3 g/m 2), high-dose cytarabine (3 g/m 2), capecitabine, thiotepa, and temozolomide.,
In melanoma, vemurafenib  and dabrafenib  in BRAF-positive patients with LM disease (LMD) demonstrated significant improvement in clinical symptoms and long-term stabilization of LMD, with survival times >18 months. The median survival of patients treated with a BRAF inhibitor combined with CTLA-4 target was 21.7 weeks, with a range of 2–235 weeks in a Randomized Controlled Trial conducted. The 14 patients who were treated with BRAF inhibitors alone had a median survival of 24.9 weeks.,
The arrival of epidermal growth factor receptor (EGFR) mutations and drugs that target them has proven to be a positive advancement in the treatment of LMD secondary to non-small cell lung cancer (NSCLC) because these patients show elevated response rates to TKIs, leading to improved progression-free survival rates., The pulsatile dosing of erlotinib at a rate of 1500 mg once weekly has been shown to reach therapeutic levels within the CSF with reported survival ranging from 2.9 months to continued survival past the study report (>25.4 months., Third-generation TKIs (e.g., Osimertinib) show promising results because of their increased CNS permeability and ability to reach high concentrations in the CSF. In the BLOOM study, Osimertinib was given at a dose of 160 mg to 41 patients with LM from EGFR-mutated advanced NSCLC whose disease had progressed on EGFR-TKI therapy. Meaningful improvements were obtained in terms of radiologic response, symptomatic improvement, CSF clearance of malignant cells, and there was a manageable toxicity profile in all patients., The second-generation ALK inhibitors, namely ceritinib and alectinib, have shown better CNS activity in several case reports of patients with crizotinib ( first-generation ALK inhibitor) resistant disease. Phase 2 clinical trial is under way to study the efficacy of ceritinib in treating patients with LM in ALK-rearranged NSCLC.,
Intrathecal trastuzumab administration has been found to be effective in LM from HER2-positive breast cancer., A phase I trial of IT has demonstrated that it is well tolerated, and many phase II clinical trials are underway to prove efficacy and confirm toxicity. The LANDSCAPE trial of HER2-positive breast cancer patients with brain metastases (which included LM metastases) with the use of combination of capecitabine and lapatinib (both oral drugs) has shown an amazing response rate of 65.9%.
Newer therapeutic approaches
Safety and efficacy of IT (via Ommaya reservoir) and intravenous nivolumab combination has been tried in combination in single center Phase I/Ib trial and has shown great promise. A dose of 20 mg nivolumab is the recommended dose.
Combinations of chemotherapy with anti-vascular endothelial growth factor inhibitors (bevacizumab) and EGFR monoclonal antibodies (cetuximab) are also being tried and has shown to be safe.
Abemaciclib, a CDK 4/6 inhibitor, is currently being used in a phase 2 clinical trial of patients with LM from NSCLC and breast cancer  and results are awaited.
The only mode of radiotherapy that treats the entire neurological milieu is craniospinal axis irradiation. It could help in relief of pain and re-establish normal CSF flow. However, problems associated with it include:
- Most of the patients have some neuraxial region previously irradiated
- Prior cytotoxic chemotherapy may have led to poor bone marrow reserve in several patients
- They may have poor bone marrow store because of exposure to cytotoxic chemotherapy
- It rarely leads to neurological recovery
- Retrospective studies in patients with breast and lung cancers showed that radiation is unlikely to improve survival.
Hence this modality is less commonly advocated in clinical practice.
Surgical procedures are usually instituted in cases of:
- Raised intracranial pressure (with symptomatic hydrocephalus) requiring ventriculoperitoneal shunting (VPS)
- Placement of ventricular access device to facilitate intra-CSF drug treatment
- Rarely for meningeal biopsy.
VPS could provide relief of symptoms and the performance status. This will allow the treating physician to propose more systemic treatments in a multidisciplinary clinic.,
Supportive care is especially significant for patients with LM because the quality of life mostly deteriorated. Steroids should be utilized sparingly but effectively, that is, it should be prescribed at the lowest dose and for the shortest time possible to prevent steroid related adverse events. Special care should be taken to manage seizures taking into consideration the interactions with systemic treatments. The need for psycho-oncological support for the patient and caregiver should be studied. Psychostimulants could be used to mitigate fatigue related to treatment, specifically radiation. Palliative focal radiation, opioids, or opioid-sparing agents is useful to control pain due to cranial and spinal nerve involvement. Unfortunately, this is often refractory if the response to treatment of the underlying disease is poor.
| Conclusion|| |
The management of leptomeningeal metastases should be done on a case-by-case basis. A multidisciplinary approach should be undertaken. The primary sites of tumor and its systemic treatment options as well as clinical/imaging findings and cytological positivity of leptomeningeal metastases should guide the treatment and its response. The histology and molecular characteristics of the malignancy should be considered for modifying the systemic treatment. Despite advances in the cancer diagnosis and treatment field, LM remains one of the most 'difficult to manage' complications of cancer; more so as the occurrence of LM is increasing with advancement of cancer treatment. The complexity in diagnosis, poor prognosis, the calamitous impact on quality of life, and diverse response to standard cancer-directed therapies are the main obstacles in the management.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]